CA2257860A1 - Inclusion complex containing indole selective serotonin agonist - Google Patents

Inclusion complex containing indole selective serotonin agonist Download PDF

Info

Publication number
CA2257860A1
CA2257860A1 CA002257860A CA2257860A CA2257860A1 CA 2257860 A1 CA2257860 A1 CA 2257860A1 CA 002257860 A CA002257860 A CA 002257860A CA 2257860 A CA2257860 A CA 2257860A CA 2257860 A1 CA2257860 A1 CA 2257860A1
Authority
CA
Canada
Prior art keywords
inclusion complex
cyclodextrin
beta
methyl
sumatriptan
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA002257860A
Other languages
French (fr)
Inventor
Lawrence John Penkler
Lueta-Ann De Kock
Darryl Vanstone Whittaker
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Farmarc Nederland BV
Original Assignee
Farmarc Nederland B.V.
Lawrence John Penkler
Lueta-Ann De Kock
Darryl Vanstone Whittaker
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Farmarc Nederland B.V., Lawrence John Penkler, Lueta-Ann De Kock, Darryl Vanstone Whittaker filed Critical Farmarc Nederland B.V.
Publication of CA2257860A1 publication Critical patent/CA2257860A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/724—Cyclodextrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/126—Acids containing more than four carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
    • Y10S530/827—Proteins from mammals or birds
    • Y10S530/843—Digestive system
    • Y10S530/847—Bile

Abstract

An inclusion complex comprises (a) an indole selective serotonin (5-HTID) agonist or a pharmaceutically acceptable salt thereof, such as for example sumatriptan, and (b) unsubstituted or substituted beta- or gamma-cyclodextrin, such as for example methyl-beta-cyclodextrin. Pharmaceutical compositions containing the inclusion complex and the use of the inclusion complex in the treatment of migraine and cluster headaches are also disclosed.

Description

CA 02257860 l998-l2-09 rNCLUSION COMPLEX CONTAINING rNDOLE

SELECTIVE SEROTONTN AGONIST

BACKGROUND OF THE INVEi~TION

THIS invention relates to an inclusion comple,Y of an indole selective serolonin (5-HT~D) agonist and an unsubstituted or substituted beta- or garnma-cyclode,Ytrin, and to pharmaceutical composi~ions containing such a complex, particularly for oral or nasal mucosal delivery, for the trealment of migraine or cluster headaches.

Sumatriptan (3-(2-dimethylaminoethyl)indol-5-yl-N-melhylmethanesulphonamide) and olher structurally relaled indole derivatives such as naratriptan, rizatriptan, zolmitriptan, eletriptan and almotriptan are selective serotonin (5-HT,D) agonists useful for the trealment of migraine. Sumatriptan is given orally or subcutaneously as the succinate salt for the treatment of migraine. Sumatriptan is rapidly absorbed following oral a~mini.stration and undergoes e,Ytensive pre-systemic metabolism, CA 022~7860 1998-12-09 W 098/02186 PCTtGB97/01872 resulting in a low bioavailability of about 14%. The bioavailability fo~lowing subcutaneous a-lmini~tration is 96%. For the acute treatment of migraine~
sumatriptan may be given in an initial dose of lOOmg by mouth and a clinical response can be e~pected between 0,- to ' ho-lrs. Alternatively, sumatriptan may be given by subcutaneous injectioll in a single dose of 6 mg with a clinical response in 10 - 1~ minutes.

Apart from the low bioavailability following oral administration of anti-migraine compo-mds such as sumatriptan~ the classical oral route of administration has limitations in the treatment of migraine due to nausea and vomiting associated with migraine attacks. Many patients are averse to self administration by subcutaneous injection, limiting this route of a~lmini.~tration.

The oral and nasal cavities have several advantages as sites for systemic drug delivery, particularly avoidance of presystemic metabolism. However, the low permeability of the membranes that line the oral and nasal cavities result in a low flux of drug. There is therefore a need to enhance drug penetration to improve bioavailability following oral or nasal m-lcosal drug delivery.

There are several methods known in the art to deliver drugs to the oral and nasal mucosae. These include buccal and sublingual tablets or lozenges, adhesive patches, gels, solutions or sprays (powder, liquid or aerosol) for the oral cavity and solutions or sprays (powder, liquid or aerosol) for the nasal cavity.

The absorption of drugs from mucosal membranes may be enhanced by (i) increasing drug solubility, (ii) pH modification to favour the unionized form of the drug, (iii) addition of mucoadhesive agents to improve contact between the delivery system and the membrane and (iv) incorporation of so-called penetration enhancers.

CA 022~7860 1998-12-09 There are a number of penetration enhancers known to influence the permeability of drugs across epithelial membranes [for a recent review see Walker, R.B and Smith. E.W. Advanced Drug Delivery Revie~vs 1996 '95-301] .

CyclodeYtrins and their derivatives have found e~;tensive application as sol~lbilizers and stabilizers due to their abilit,v to form inclusion compleYes with a wide variety of compounds [see (J. Szejtli. C~ clocf~xtrin Techf1010~;, Kluwer Academic Press) and (J. Szejtli & K-H Frommin_, Cyclo~ex~ri)?s in Pharmacy, Kluwer Academic Press)]. Cyclode~trins have been used to enhance intestinal absorption of drugs primaril,v throuoh increasino solubility.Recently. cyclodextrins have been shown to have positive and ne~ative effects on transdermal penetration of drugs [see (Loftsson. T. et al International Journal of Pharmaceutics 199~ 58), (Vollmer~ U. et al. International Journal of Pharmaceutics 1993, 99~ ~1-58), (Legendre. J.Y.
et al. European Journal of Pharmaceutical Sciences 199~, 3~ 311-3~) and (Vollmer, U. et al Journal of Pharmacy and Pharmacology 199~ 46, 19-~2)~ .
Cyclode,Ytrins may improve nasal absorption of dru~s [see (Merkus~ F.W. et al. Pharmaceutical Research 1991, 8~ 588-59~) and (Shao~ Z. et al Pharmaceutical Research 199~, 9, 11~7-1163)] and enhance absorption from sublingual a(lmini.~tration of drug/cyclode,Ytrin comple~es. CyclodeYtrins also protect nasal mucosal damage by penetration enhancers [see Jabbal-Gill, I. et al. European Journal of Pharmaceutical Sciences 1994~ 1(5)~ 229-~36]

Cyclodextrins are water soluble cone-shaped cyclic oligosaccharides containing 6, 7 or 8 glucopyranose units. The interior or 'cavity" of the cone is hydrophobic whilst the exterior is hydrophilic. The size of the cavit,v increases with increasing number of glucose units. Several cvclode~trin derivatives such as alkyl, hydro,Yyalkyl and sulfoalkyl ethers have been prepared with improved solubility [see (J. Szejtli & K-H Fromming~
Cyclodextrins in Pharmacy, Kluwer Academic Press) and (Stella~ V.J. et al CA 022s7860 1998-12-09 Pharmaceutical Research 1995, 1~ (9) S205)1. Suitably sized hydrophobic''~uest" molecules may enter the ~'host' cavitv to form a classical host-~Juest 'inclusion compound" or ''inclusion complex' witll either the elltire guest molecule included or only a portion thereof~ The driving mechanism for cyclodextrin inclusion complexation is the affinitv of the hydrophobic guest molecule for tl1e cavity of the cyclodextrin host molec-lle with displacement of cavitv water moiecules to a thermodynamicallv more stable state. The term 'complex srability" or stability of a given inclusion comple:~ refers to the association/dissociation equilibrium of host and guest in solution.
Complex stability depends on the number of intermolecular bonding interactions between the host and guest. ~/ran der waals forces and hvdrophobic interactions are the main interactions stabilizing inclusion complexes (Bergeron, R.J. et al. Jol~rnal of th~ e~ ican Chemical Societv 1977~ 99~ 51~16). Depending on the nature and position of hydroaen bonding functionalities on a given guest, there may be hydrogen bondin~ between the guest and hydroxyl groups of the cvclodextrin or other hydrogen bonding groups in the case of cyclode~trin derivatives. Ionic interactions between the host and 17uest are also possible in the case of ionic cyclodextrins such as sulphobutyl ethers (Stella, V.J. et al Pharmaceutical Research 199~, 1' (9) S~05).

Cyclodextrin inclusion complexes may be prepared on the basis of liquidstate, solid state or semi-solid state reaction between the components (J.
Szejtli, Cyclodex~ri~Z Technology, Kluwer Academic Press). The first is accomplished by dissolving the cyclodextrin and guest in a suitable solvent or mixture of solvents and sLlbsequently isolating the solid state complex by crystallization, evaporation, spray drying or freeze drying. In the solid state method, the two components may be screened to ~miform particle size and thoroughly mixed whereafter they are ground in a high energy mill with optional heating, screened and homogenized. In the semi-solid state, the two components are kneaded in the presence of small amounts of a suitable solvent, and the complex so-formed, is dried, screened and homogenized.

The liquid state reaction ~enerally provides optimum conditions for completeness of reaction. Depending on solvent conditions, the dissolved inclusion complex e~ists in equilibrium between uncomplexed host and guest and complexed host/guest.

SUMMARY OF THE INVENTION

~ccording to a first aspect of the invention there is provided an inclusion complex of (a) an indole selective serotonin (~-HTID) a_onist or a pharmaceutically acceptable salt thereof and (b) an ~msubstituted or substiluted beta- or gamrna- cyclodextrin.

By an indole selective serotonin (~-HTID) agonist there is meant a compound whicll includes the indole structure, which structure will generally be substituted, and which has selective serotonin (~-HT,D) agonist activity.

The indole selective serotonin (~-HT,D) agonist is preferably selected from compounds having the formuJa:
X

~N

~vherein X and Y represent suitable substitutions, more preferably from the group consisting of sumatriptan, naratriptan, ri~atriptan, zolmitriptan, elelriptan and almotriptan or a pharmaceutically acceptable salt thereof.
Thus. compound (a) may be used in the form of the free base or in the form of a pharmaceutically acceptable salt such as a hydrochloride, succinate, citrate, furnarate, sulphate, benzoate, or maleate salt.

The inclusion complex preferably has a stoichiometry of (a) to (b) of 1:1 CA 022=,7s60 1998-12-09 mol/mol.

The inclusion compleY is preferably an incl-lsion comple,Y of sumatriptan free base and methyl-beta-cyclodeYtrin or of sumatriptan succinate and methyl-beta-cyclode~ctrin which has substantially the ~-rav powder diffraction pattern of Figure 4 or Figure 5.

According to a second aspect of the invention there is provided a pharmaceutical composition which comprises as an active ingredient an inclusion compleY of (a) an indole selective serotonin (~-HT,~) agonist or a pharmaceuticallv acceptable salt thereof and (b) an unsubstituted or substituted beta- or gamma-cyclodextrin.

The pharmaceutical composition is preferably for use in the treatment of mioraine and cluster headaches.

The pharmaceutical composition is preferablv adapted for oral or nasal mucosal delivery.

BRIEF DESCRIPTION OF THE D~AWINGS

The invention will now be described in more detail? by way of eYample only, with reference to the accompanying drawin,s in which:

Figure 1 shows a differential scanni~lg calorimetry thermogram of sumatriptan succinate with the onset melting temperature of 166~C and sharp endothermic melting peak at 167,9CC;

Figure 2 shows a differential scanning calorimetry thermogram of a 1:1 kneaded comple~c of sumatriptan succinate and methyl-beta-cyclodeYtrin obtained from EYample l;

CA 022~7860 1998-12-09 Figure 3 shows a differential scanning calorimetry thermogram of a 1:1 kneaded complex of sumatriptan succinate and methyl-beta-cyclodextrin containing I molar equivalent of tromethamine obtained from E~ample ~:

Figure 4 shows an X-ray powder diffraction pattern of the 1:1 kneaded comple~ of sumatriptan succinate and methyl-beta-cyclode~ctrin obtained from E~cample l;

Figure 5 shows an ~-ray powder diffraction pattern of the 1:1 kneaded complex of sumatriptan succina~e and methyl-beta-cyclodextrin containing one molar equivalent of tromethamine obtained from Example 2: and Figure 6 sho~vs a cut-away perspective of the geometry optimized molecular mechanical model of an inclusion complex of sumatriptan (pale grey) in beta-cyclode~trin (dark ~rey).

DESCRIPTION OF EMBODIMENTS

The crux of the invention is an inclusion cornplex of (a) an indole selective serotonin (5-HT,D) agonist or a pharmaceutically acceptable salt thereof and (b) an unsubstituted or substituted beta- or ~amma-cyclode~trin.

Examples of suitable compounds (a) are sumatriptan, naratriptan, rizatriptan, zolmitriptan, eletriptan and almotriptan. The compound may be used in the form of the free base or in the form of a pharmaceutically acceptable salt such as a hydrochloride, succinate, citrate, fumarate sulphate, benzoate, or maleate salt or the like.

The second component of the inclusion comple~c is an unsubstituted or CA 022~7860 1998-12-09 substituted beta- or gamma-cyclodextrin.

Highlv ~vater soluble cyclodextrins S-ICII as ~-hydrox,vpropylated or meth,vlated or sulphoalkylated derivatives of beta-cyclode~;trin are the preferred cyclodextrins of the invention. Gamma-c,vclodextrin or ~-hvdro~ypropylated or methvlated or sulphoalkylated derivatives of gamma-cyclodextrin ma,v also be used in the same manner as the corresponding preferred beta-c,vclodextrin derivatives. The degree of substitution of the c,vclodextrin derivatives may vary between I to ~0 substituents per cyclodextrin molecule but more preferably between ~ to 15 substituents per cyclodextrin molecule. When the c,vclode:ctrin is ~-hydrox,vpropyl-beta-cyclodextrin~ the preferred degree of substitution is bet~veen 3.9 alld ~.1 hvdroxypropyl groups per cyclodextrin molecule. When the c,vclodextrin is methyl-beta-cyclodextrin~ the preferred degree of substitution is between l 8 and ~ methyl groups per glucose unit.

The inclusion complex of the invention may be prepared from aqueous solutions~ slurries or pastes of the indole derivative and cyclode~trin according to conventional methods. The molar ratio of indole derivative to cyclodextrin may vary between 1:1 to 1:10 but more preferabl,v between 1:1 to 1:5. Solutions are prepared by dissolving the cvclodextrin in a sufficient quantity of purified deionised water which may be optionally buffered between pH 7,4 to 8,5. The indole derivative is added to the solution with stirring until dissolved. The solution may be used in the preparation of liquid delivery systems such as drops, sprays or aerosols. Where a solid inclusion complex is desired, the solution or slurry may be dried by spray drying or freeze drying.

Alternatively, the indole derivative and cyclodextrin are mixed. The powder mixture is wetted with water, optionally containing a buffer pH 7,4 - 8.5.
while mixing vigorously until a paste is formed. The paste is mixed for 0,''5 to ~ hours and dried in an oven or in vacuo at elevated temperature. The CA 022~7860 1998-12-09 dried comple,Y is crushed and sieved to tl~e desired particle size.

A pharmaceutically acceptable buffer, capable of b~lffering in the pH ran( e 7~ ,5 may be used in the formation of the inclusioll comple~. particularly when the indole derivative is present as a salt. Preferred buffers include tromethamine, triethanolamine, diethallolamine. phosphate buffer, sodium bicarbonate, and sodium carbonate. The concentration of the b-lffer may vary from 0,5 to ~ molar equivalents relative to the indo~e.

The second aspect of the invention is a pharmaceLItical composition ~vhich comprises as an active ingredient an inclusion comple~ as described above.

The pharmaceutical composition of the inven[ion is of particular application in the treatment of migraine and cluster headaches.

Further, the pharmaceutical composition of the invention is preferably adapted for oral or nasal mucosal delivery.

The ~lmini.stration of an anti-migraine drug throuah the mucosal tissue of the nose or mouth avoids the problems associated with administration of indole serotonin agonists by injection (i.e. patient aversion and painful administration) and oral administration (i.e. slow onset of action~ lo~v bio-availability and poor compliance due to nausea and vomiting associated with migraines) .

Absorption of the drug from the pharmaceutical composition of the invention is rapid such that the drug reaches the systemic circulation almost as fast as through injection and appreciably faster than oral ~(lmini.stration, which is highly advantageous for the rapid relief of migraine attack or cluster headache.

Further, the unpleasant taste and irritant properties of the active principle are CA 022~7860 l998-l2-09 reduced by presenting the drug to the nasal or oral mucosal membranes in the form of a cyclodeYtrin inclusion complex.

The present invention achieves these advantages bv molecular encaps~llation of the anti-migraine indole drug in a cvclodextrin, so forming a molecular inclusion complex which may be used in the solid form for the preparation of sublingual or buccal tablets, buccal patches or nasal inhalatioll powders (insufflations). The inclusion complex may be llsed in the liquid state for the preparation of metered dose sprays~ drops or pressurized aerosols for nasal or oral administration. The complex according to the invention may be incorporated into a shearform matrix designed for immediate release as described in ~uisz Technologies Ltd patents (Eur. Pat. Appl. EP 9~-6~0038 and PCT Int. Appl. WO 95/34~9J).

According to the invention, the indole nucleus of selective serotonin (5-HTID) agonists has been found to be readily included in the cavitv of beta-cyclodextrins such as hydroxypropyl-beta-cyclodeYtrin and methyl-beta-cyclode~trin to form molecular inclusion complexes with a 1:1 mol/mol stoichiometry. Inclusio!l compleYes of a variety of indole-based serotonin agonists may therefore be prepared according to methods known in the art such as spray drying, freeze drying and kneading, as described above. The complexes accordin to the invention may also be incorporated into microspheres by methods appreciated in the art. The complexes accordin_ to the invention are stable, amorphous and highly water soluble.

Penetration enhancers may be used to promote the passage of the indole derivative across the mucosal membranes. Tvpical permeation enhancers include fatty acids and their salts such as sodium caprate, sodium caprylate and sodium oleate, sodium laurate, and bile salts such as sodium glycodeoxycholate, sodium glycocholate, sodium cholate and sodium taurodeoxycholate. Other penetration enhancers may include tensides, ionic surfactants such as sodium lauryl sulphate, or non-ionic surfactants such as CA 022~7860 1998-12-09 Il polyethylene glycol 660 hydro~cystearate or polyoxyethylene lauryl ethers~
fusidates such as sodium taurodihydrofusidate. Other specific enhancers include azone and chitosan. Combinations of permeation enhancers such as polyoxyethylene ~ lauryl ether and sodium glycocholate or mi~ed micelles such as sodium caprate and sodium glycocholate may also be used. The penetration enhancers may also be used in combination with beta or gamma-cyclodextrins or their methyl, hydro~cypropyl or sulphoalkyl derivatives.
Typical concentrations of permeation enhancers are between 0,1 % to ~%, more preferably between 0,~% to 3~/O by weioht of the composition.

As stated above, the serotonin (S-HTID) agonist may be used in the form of the free base or a pharmaceutically acceptable salt. When acidic penetration enhancing excipients are used such as bile acids or fatty acids or pharmaceutically acceptable salts of bile acids or fatty acids, salt formation between the basic component of the serotonin (S-HT,D) agonists and the acidic component of the bile or fatty acid may occur.

Buffering agents may be incorporated into the pharmaceutical composition of the invention to control the microenvironmental pH surrounding the drug delivery system in the alkaline range, so as to maximize the percentage of the unionized form of the drug. Drugs in the unionized form cross mucosal membranes more readily than the corresponding unionized form.

Liquid compositions suitable for nasal or oral administration may contain a suitable quantity of viscosity modifying agents such as hypromellose or carbopol 934P and preservative agents such as chlorhe~cidine gluconate or thiomersal.

Oral compositions may contain suitable flavouring and sweetening agentssuch as cherry, mint, spearmint, vanilla, aspartame, sucrose, ~ylitoh saccharin and the like.

CA 022~7860 1998-12-09 Typical sublingual or buccal tablets may include lubricants such as magnesium stearate, calcium stearate and sodium stearvl fumarate to facilitate tablet compression~ diluenIs sucl1 as lactose. microcrvstalline cellulose, maize starch and the like and m-lcoadhesive a~ents such as chitosan. carbopol 934P. and hydroxvpropylcell-llose and the like.

Typical disintegrants to enhance sublingual tablet disintegration mav include sodium carboxymethylcellulose. sodium starch glvcolate~ polvplasdolle ~L.
and dried starch.

The following examples illustrate the present invention.

Sumatriptan succinate ( I g) and methyl-beta-cyclodextrin (3,18) are mixed in a mortar. Purified deionised water (2ml) is added in aliquots with mixing to form a uniform paste. Mixing is continued for 0~5 hours and the paste is transferred to a vacuum oven and dried at 40~C and ~ millibar. The dried complex is crushed with a pestle and passed through a 60 mesh (250 micron) sieve. The complex contains 23,0 % m/m (mass/mass) sumatriptan succinate as determined by HPLC.

Tromethamine (0,293g) was dissolved in 5 ml purified deionised water.
Sumatriptan succinate (Ig) and methyl-beta-cyclodextrin (3,18g) are mixed in a mortar. The tromethamine solution is added in aliquots with mixing to form a uniform paste. Mixing is continued for 0,5 hours and the paste is transferred to a vacuum oven and dried at 40~C and ~ millibar. The dried complex is crushed with a pestle and passed through a 60 mesh (250 micron) sieve. The complex contains 21,7 % m/m sumatriptan succinate as determined by HPLC.

The unit composition of a sublingual tablet containin(1 tl1e equivalent of 'O
mo sumatriptan base is as follows:

Sumatriptan/methyl-be~a-cyclodextrin complex ~from Example ~) 130m~
Lactose NF ~Omg Ma~nesium stearate I mg The complex is blended with the lactose. The lubricant is screened in and the mixhlre is blended and f'ormed into sublingual tablets by compression at 10 - 30N.

The unit composition of a sublingual tablet containing the equivalent of ~0 mg sumatriptan base is as follows:

Sumatriptan/methyl-beta-cyclodextrin complex (from Example 1) l'~mg Xylitol ~ 8mg Sodium caprate 3.75m(J
Magnesium stearate Img The complex is blended with the xylitol and sodium caprate. The lubricant is screened in and the mixture is blended and formed into subling-lal tablets by compression at 10 - 30N.

Hydroxypropyl-beta-cyclodextrin (3,39g) is dissolved in purified deionised water (8ml) buffered to pH 7,4 witl1 phosphate buff'er. Sumatriptan succinate (Ig) is added to the solution with stirring. The solution is stirred f'or ~0 CA 022s7860 1998-12-09 minutes and then sodium caprate (25mg) and chlorhe~idine gluconate (0,01%) is added. The volume is adjusted to 10 ml by addition of phosphate buffer pH 7,4 and the tonicity of the final sol-ltion is adjusted with sodium chloride to 300 mOsm/kg. The solution is f1ltered and filled into a metered dose nasal spray bottle. Each 0,1 ml metered dose contains 10 mg sumatriptan succinate suitable for nasal a~mini.~tration.

Referring now to the drawings, Figure 1 shows a differential scanning calorimetry thermogram of s-lmatriptan succinate with the onset meltillg temperature of 166~C and sharp endothermic meltincg peak at 167,9~C. The thermogram was recorded on a Perkin-Elmer DSC7 calorimeter with a heating rate of 5~C per minute. A sample mass of 1~36 mg was used.

Figure 2 shows a differential sc~T~nin,, calorimetry thermogram of a 1:1 kneaded complex of sumatriptan succinate and methyl-beta-cyclodextrin obtained from Example 1. The characteristic melting endotherm of sumatriptan succinate shown in Figure 1 is absent. providing evidence of inclusion complexation between sumatriptan and methyl-beta-cyclodextrin.
Characteristic decomposition of methyl-beta-cyclodextrin is seen from 175~C. Experimental conditions where as described in Exarnple 1, except that a sample mass of I 1,1 mg was used to provide a sumatriptan succinate response equivalent to Example 1.

Figure 3 shows a differential scanning calorimetr,v thermogram of a 1:1 kneaded complex of sumatriptan succinate and methyl-beta-cyclodextrin containing I molar equivalent of tromethamine obtained from Example 2.
The characteristic melting endothermy of sumatriptan succinate shown in Figure 1 is absent. An endotherm corresponding to the free base at 89~C is also absent providing evidence of inclusion complexation between sumatriptan and methyl-beta-cyclodextrin. Characteristic decomposition of methyl-beta-cyclodextrin is seen from 1 75~C. Experimental conditions were as described in Example 1 except that a sample mass of 12,42 mg was used CA 022~7860 1998-12-09 to provide a sumatriptan succinate response equivalent to E~ample 1.

Figure 4 sho~vs an X-ray powder diffraction pattern of tlle 1:1 kneadedcomplex of sumatriptan succinate and meth,vl-beta-c,vclodextrin obtained from Example 1. The absence of resolved sharp peaks characteristic of crystalline sumatriptan succinate indicates inclusion comple~ation with resultant loss of crystallinity. The resulting diffraction pattern is characteristic of an amorphous solid.

Figure 5 sho~,vs an X-ray powder diffraction pattern of the 1:1 kneadedcomple,Y of sumatriptan succinate and methyl-beta-cyclode,Ytrin containing I molar equivalent of trornethamine obtained from E.~ample 2. The absence of resolved sharp peaks characteristic of crystalline sumatriptan succinate and tromethamine indicates inclusion comple~ation witll resultant loss of cr,vstallinity, The resulting diffraction pattern is characteristic of an amorphous solid.

Figure 6 shows a cut-away perspective of the geometry optimised molecular mechanical model of an inclusion complex of sumatriptan (pale grey) in beta-cyclodextrin (dark grey). The indole nucleus fills the cavity with the pendant dimethylaminoethyl (bottom) and metl1anesulphonamide (top) side chains extending out of the cavity.

Claims (18)

1 An inclusion complex of (a) an indole selective serotonin (5-HT ID) agonist or a pharmaceutically acceptable salt thereof and (b) an unsubstituted or substituted beta-or gamma-cyclodextrin.
2 An inclusion complex accordin to claim 1 wherein (a) is sumatriptan or a pharmaceutically acceptable salt thereof.
3 An inclusion complex accordng to claim 1 wherein (a) is selected from the group consisting of naratriptan rizatriptan. zolmitriptan eletriptan and almotriptan and the pharmaceutically acceptable salts thereof.
4 An inclusion complex according to any one of claims 1 to 3 wherein (b) is selected from the group consisting of 2-hydroxypropyl-beta-cyclodextrins a methylated-beta-cyclodextrins and a sulphoalkylated beta-cyclodextrin.
An inclusion complex according to any one of claims 1 to 4 wherein (b) has a degree of substitution between 1 to 20 substituents per cyclodextrin molecule.
6 An inclusion complex according to claim 5 wherein (b) has a degree of substitutioll between 3 to 15 substituents per cyclodextrin molecule.
7 An inclusion complex according to any one of claims 1 to 3 wherein (b) is 2-hydroxypropyl beta-cyclodextrin with a degree of substitution between 3,9 and 5,1 hydroxypropyl groups per cyclodextrin molecule.
8 An inclusion complex according to any one of claims 1 to 3 where (b) is methyl-beta-cyclodextrin with a degree of substitution between 1,8 and 2 methyl groups per glucose unit.
9 An inclusion complex of sumatriptan free base and methyl-beta-cyclodextrin.
An inclusion complex of sumatriptan succinate and methyl-beta-cyclodextrin.
11 An inclusion complex of sumatriptan succinate and methyl-beta-cyclodextrin having substantially the X-ray powder diffraction pattern of Figure 4 or Figure 5.
12 An inclusion complex according to any one of claims 1 to 11 wherein the inclusion complex has a stoichiometry of (a) to (b) of 1:1 mol/mol.
13 A pharmaceutical composition comprises as an active ingredient an inclusion complex of (a) an indole selective serotonin (5-HT ID) agonist or a pharmaceutically acceptable salt thereof and (b) an unsubstituted or substituted beta- or gamma-cyclodextrin.
14 A pharmaceutical composition according to claim 13 wherein the inclusion complex is as defined in any one of claims 2 to 12.
A pharmaceutical composition according to claim 13 or claim 14 for use in the treatment of migraine or cluster headaches.
16 A pharmaceutical composition according to any one of claims 13 to 15 formulated for oral or nasal mucosal delivery.
17 The use of an inclusion complex of (a) an indole selective serotonin (5-HT ID) agonist or a pharmaceutically acceptable salt thereof and (b) an unsubstituted or substituted beta- or gamma-cyclodextrin in the manufacture of a medicament for use in the treatment of migraine or cluster headaches.
18 The use according to claim 17 wherein the inclusion complex is as defined in any one of claims 2 to 12.
CA002257860A 1996-07-11 1997-07-11 Inclusion complex containing indole selective serotonin agonist Abandoned CA2257860A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ZA96/5889 1996-07-11
ZA965889 1996-07-11

Publications (1)

Publication Number Publication Date
CA2257860A1 true CA2257860A1 (en) 1998-01-22

Family

ID=25585787

Family Applications (2)

Application Number Title Priority Date Filing Date
CA002259418A Abandoned CA2259418A1 (en) 1996-07-11 1997-07-11 Pharmaceutical composition containing acid addition salt of basic drug
CA002257860A Abandoned CA2257860A1 (en) 1996-07-11 1997-07-11 Inclusion complex containing indole selective serotonin agonist

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CA002259418A Abandoned CA2259418A1 (en) 1996-07-11 1997-07-11 Pharmaceutical composition containing acid addition salt of basic drug

Country Status (10)

Country Link
US (1) US6255502B1 (en)
EP (1) EP1024833A1 (en)
JP (2) JP2000505090A (en)
KR (2) KR20000022239A (en)
CN (1) CN1230123A (en)
AU (2) AU3455297A (en)
BR (2) BR9710241A (en)
CA (2) CA2259418A1 (en)
IL (2) IL127955A0 (en)
WO (2) WO1998002187A1 (en)

Families Citing this family (138)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9706089D0 (en) * 1997-03-24 1997-05-14 Scherer Ltd R P Pharmaceutical composition
US20040043071A1 (en) * 2002-06-21 2004-03-04 Pauletti Giovanni M. Intravaginal mucosal or transmucosal delivery of antimigraine and antinausea drugs
WO1999040898A2 (en) * 1998-02-12 1999-08-19 Centrapharm Inc. Sublingual drug formulations having combined rapid onset of action and long lasting therapeutic effect
DE19810951B4 (en) * 1998-03-13 2005-09-29 Ciba Speciality Chemicals Holding Inc. Use of a textile material as a transdermal delivery system and process for its preparation
US6541669B1 (en) * 1998-06-08 2003-04-01 Theravance, Inc. β2-adrenergic receptor agonists
GB9816556D0 (en) * 1998-07-30 1998-09-30 Pfizer Ltd Therapy
US6255334B1 (en) * 1998-10-30 2001-07-03 Pfizer Inc 5HT 1 receptor agonists and metoclopramide for the treatment of migraine
US6849263B2 (en) * 1998-12-21 2005-02-01 Generex Pharmaceutical Incorporated Pharmaceutical compositions for buccal delivery of pain relief medications
US7087215B2 (en) * 1998-12-21 2006-08-08 Generex Pharmaceuticals Incorporated Methods of administering and enhancing absorption of pharmaceutical agents
DE19901085C2 (en) * 1999-01-14 2003-12-18 Lohmann Therapie Syst Lts Transdermal therapeutic system with a self-adhesive matrix containing organic acid addition salts of morphine or morphine type alkaloids
GB9915231D0 (en) 1999-06-29 1999-09-01 Pfizer Ltd Pharmaceutical complex
GB9928578D0 (en) * 1999-12-03 2000-02-02 Zeneca Ltd Pharmaceutical formulations
GB9930026D0 (en) * 1999-12-21 2000-02-09 Univ Sheffield Novel compounds of unsaturated fatty acids
US6610271B2 (en) * 2000-05-10 2003-08-26 University Of Kentucky Research Foundation System and method for intranasal administration of lorazepam
US20060083691A1 (en) * 2000-05-10 2006-04-20 Wermeling Daniel P Intranasal opioid compositions, delivery devices and methods of using same
US20040115133A1 (en) * 2000-05-10 2004-06-17 Wermeling Daniel P. Intranasal opioid compositions
AU2001286518A1 (en) * 2000-08-15 2002-02-25 University Of Kentucky Research Foundation Programmable multi-dose intranasal drug delivery device
BRPI0115531B1 (en) * 2000-11-22 2015-10-13 Rxkinetix Inc therapeutic composition useful for treating mucositis at a mucosal site as a side effect of cancer therapy
US20040176359A1 (en) * 2001-02-20 2004-09-09 University Of Kentucky Research Foundation Intranasal Benzodiazepine compositions
EP1372605A2 (en) * 2001-03-27 2004-01-02 Galen (Chemicals) Limited Intravaginal drug delivery devices for the administration of an antimicrobial agent
EP1390073A2 (en) * 2001-05-03 2004-02-25 Allergan, Inc. Compositions having enhanced pharmacokinetic characteristics
US20020198209A1 (en) 2001-05-03 2002-12-26 Allergan Sales Inc. Compositions having enhanced pharmacokinetic characteristics
US20070122353A1 (en) 2001-05-24 2007-05-31 Hale Ron L Drug condensation aerosols and kits
US6737042B2 (en) 2001-05-24 2004-05-18 Alexza Molecular Delivery Corporation Delivery of drug esters through an inhalation route
US20030051728A1 (en) 2001-06-05 2003-03-20 Lloyd Peter M. Method and device for delivering a physiologically active compound
US6759029B2 (en) 2001-05-24 2004-07-06 Alexza Molecular Delivery Corporation Delivery of rizatriptan and zolmitriptan through an inhalation route
DE10141650C1 (en) 2001-08-24 2002-11-28 Lohmann Therapie Syst Lts Safe transdermal therapeutic system for administration of fentanyl or analogous analgesics, having matrix layer of carboxy group-free polyacrylate adhesive providing high permeation rate
US6770625B2 (en) * 2001-09-07 2004-08-03 Nobex Corporation Pharmaceutical compositions of calcitonin drug-oligomer conjugates and methods of treating diseases therewith
US7030082B2 (en) * 2001-09-07 2006-04-18 Nobex Corporation Pharmaceutical compositions of drug-oligomer conjugates and methods of treating disease therewith
EP1446100B1 (en) * 2001-11-14 2011-05-04 Durect Corporation Injectable depot compositions and uses thereof
US20070196415A1 (en) * 2002-11-14 2007-08-23 Guohua Chen Depot compositions with multiple drug release rate controls and uses thereof
KR20040058101A (en) * 2001-11-14 2004-07-03 알자 코포레이션 Catheter injectable depot compositions and uses thereof
WO2003063927A2 (en) * 2001-11-16 2003-08-07 Eisai Co. Ltd Compositions and methods to treat gastrointestinal disorders
DE10157475A1 (en) 2001-11-23 2003-06-18 Hans-Hermann Gerdes Methods and means for influencing intercellular communication and intercellular organelle transport
US20030158118A1 (en) * 2001-11-26 2003-08-21 Weidner Morten Sloth Combination of cimetidine and cysteine derivatives for treating cancer
US20030220301A1 (en) * 2002-02-14 2003-11-27 Sonus Pharmaceuticals, Inc. Metformin salts of lipophilic acids
AU2003241464A1 (en) * 2002-05-17 2003-12-02 Eisai Co., Ltd. Compositions and methods using proton pump inhibitors
KR100469995B1 (en) * 2002-05-20 2005-02-05 안국약품 주식회사 Matrix Patch Containing Bronchodilators
US20040001889A1 (en) 2002-06-25 2004-01-01 Guohua Chen Short duration depot formulations
EP1594467A4 (en) * 2002-07-05 2008-10-22 Collegium Pharmaceutical Inc Abuse-deterrent pharmaceutical compositions of opioids and other drugs
US10004729B2 (en) 2002-07-05 2018-06-26 Collegium Pharmaceutical, Inc. Tamper-resistant pharmaceutical compositions of opioids and other drugs
US8840928B2 (en) 2002-07-05 2014-09-23 Collegium Pharmaceutical, Inc. Tamper-resistant pharmaceutical compositions of opioids and other drugs
US8557291B2 (en) 2002-07-05 2013-10-15 Collegium Pharmaceutical, Inc. Abuse-deterrent pharmaceutical compositions of opioids and other drugs
JP4569080B2 (en) * 2002-07-17 2010-10-27 大正製薬株式会社 Nasal composition
DE60226282T2 (en) * 2002-07-31 2009-09-17 Alza Corp., Mountain View INJECTABLE DEPOT COMPOSITIONS AND THEIR USE
WO2004011054A2 (en) * 2002-07-31 2004-02-05 Alza Corporation Injectable multimodal polymer depot compositions and uses thereof
US20040122065A1 (en) * 2002-11-12 2004-06-24 Lerner E. Itzhak Pharmaceutical compositions and dosage forms for buccal and sublingual delivery of tizanidine and methods of administering tizanidine sublingually or buccally
US7524515B2 (en) * 2003-01-10 2009-04-28 Mutual Pharmaceuticals, Inc. Pharmaceutical safety dosage forms
GB0300531D0 (en) 2003-01-10 2003-02-12 West Pharm Serv Drug Res Ltd Pharmaceutical compositions
US20080213363A1 (en) * 2003-01-23 2008-09-04 Singh Nikhilesh N Methods and compositions for delivering 5-HT3 antagonists across the oral mucosa
WO2008127609A1 (en) * 2007-04-11 2008-10-23 Mccarty John A Melatonin tablet and methods of preparation and use
WO2004076403A1 (en) * 2003-02-24 2004-09-10 Transform Pharmaceuticals, Inc. Sumatriptan crystalline forms, pharmaceutical compositions and methods
US10172810B2 (en) 2003-02-24 2019-01-08 Pharmaceutical Productions, Inc. Transmucosal ketamine delivery composition
ES2414084T3 (en) * 2003-02-24 2013-07-18 Pharmaceutical Productions Inc. Transmucosal drug delivery system
US9358296B2 (en) 2003-02-24 2016-06-07 Pharmaceutical Productions Inc. Transmucosal drug delivery system
US9254294B2 (en) 2003-02-24 2016-02-09 Pharmaceutical Productions Inc. Transmucosal hormone delivery system
US9498454B2 (en) 2003-02-24 2016-11-22 Pharmaceutical Productions Inc. Transmucosal drug delivery system
US20040248846A1 (en) * 2003-04-22 2004-12-09 Nastech Pharmaceutical Company Inc. Intranasal administration of triptans
US7306812B2 (en) 2003-05-09 2007-12-11 Cephalon, Inc. Dissolvable backing layer for use with a transmucosal delivery device
US7276246B2 (en) * 2003-05-09 2007-10-02 Cephalon, Inc. Dissolvable backing layer for use with a transmucosal delivery device
US20040234914A1 (en) 2003-05-21 2004-11-25 Alexza Molecular Delivery Corporation Percussively ignited or electrically ingnited self-contained heating unit and drug-supply unit employing same
CA2536530A1 (en) * 2003-10-01 2005-04-14 Taro Pharmaceuticals U.S.A., Inc. Method of preparing 4-amino-1h-imidazo(4,5-c)quinolines and acid addition salts thereof
AU2004285535A1 (en) * 2003-10-31 2005-05-12 Alza Corporation Compositions and dosage forms for enhanced absorption of gabapentin and pregabalin
RS20050835A (en) * 2004-01-06 2007-08-03 Panacea Biotec Ltd., Compositions of buccal dosage forms for extended drug release and the process of preparing such compositions
GB0400804D0 (en) 2004-01-14 2004-02-18 Innoscience Technology Bv Pharmaceutical compositions
SI1708722T1 (en) * 2004-01-28 2014-10-30 The Regents Of The University Of California Novel interstitial therapy for immediate symptom relief and chronic therapy in interstitial cystitis
GB0406445D0 (en) * 2004-03-23 2004-04-28 Astrazeneca Ab Combination therapy
CN101084016A (en) * 2004-04-15 2007-12-05 克艾思马有限公司 Compositions capable of facilitating penetration across a biological barrier
US20070219131A1 (en) * 2004-04-15 2007-09-20 Ben-Sasson Shmuel A Compositions capable of facilitating penetration across a biological barrier
US7622130B2 (en) 2004-05-19 2009-11-24 Los Angeles Biomedical Research Institute at Harbor UCLA-Medical Center Methods and compositions for the non-surgical removal of fat
US7754230B2 (en) * 2004-05-19 2010-07-13 The Regents Of The University Of California Methods and related compositions for reduction of fat
US20060127468A1 (en) 2004-05-19 2006-06-15 Kolodney Michael S Methods and related compositions for reduction of fat and skin tightening
US20060002989A1 (en) * 2004-06-10 2006-01-05 Ahmed Salah U Formulations of sumatriptan for absorption across biological membranes, and methods of making and using the same
EP1765292B1 (en) 2004-06-12 2017-10-04 Collegium Pharmaceutical, Inc. Abuse-deterrent drug formulations
US7244765B2 (en) * 2004-06-25 2007-07-17 Cytokine Pharmasciences, Inc Guanylhydrazone salts, compositions, processes of making and methods of using
GB0416861D0 (en) * 2004-07-29 2004-09-01 Quadrant Drug Delivery Ltd Composition
CN101005826B (en) * 2004-08-17 2011-08-17 荷兰联合利华有限公司 Hair care composition comprising a dendritic compositions
US20060051413A1 (en) * 2004-09-08 2006-03-09 Chow Sing S M Method of enhancing absorptions of transmucosal administration formulations
US20090227690A1 (en) * 2004-09-27 2009-09-10 Cargill, Incorporated Cyclodextrin Inclusion Complexes and Methods of Preparing Same
DK1802291T3 (en) * 2004-10-04 2012-03-26 Univ Minnesota Calixaren-based peptide conformation mimetic compounds, methods of application and methods of preparation
FR2876910B1 (en) * 2004-10-21 2007-04-13 Pierre Fabre Medicament Sa COMPLEX COMPRISING MEQUITAZINE, CYCLODEXTRIN AND INTERACTION AGENT
US20060142234A1 (en) * 2004-12-23 2006-06-29 Guohua Chen Injectable non-aqueous suspension
US20110039943A1 (en) * 2005-03-14 2011-02-17 Robert Alonso Methods for treating skin disorders with topical nitrogen mustard compositions
US7872050B2 (en) * 2005-03-14 2011-01-18 Yaupon Therapeutics Inc. Stabilized compositions of volatile alkylating agents and methods of using thereof
US8501818B2 (en) * 2005-03-14 2013-08-06 Ceptaris Therapeutics, Inc. Stabilized compositions of alkylating agents and methods of using same
JP5011776B2 (en) * 2005-03-28 2012-08-29 大正製薬株式会社 Copper compound composition
CN101223182A (en) * 2005-06-13 2008-07-16 嘉吉公司 Cyclodextrin inclusion complexes and methods of preparing same
KR20080023682A (en) * 2005-06-13 2008-03-14 카아길, 인코포레이팃드 Cyclodextrin inclusion complexes and methods of preparing same
US20070020186A1 (en) * 2005-07-22 2007-01-25 Alpex Pharma S.A. Solid dosage formulations of narcotic drugs having improved buccal adsorption
EA200800397A1 (en) * 2005-08-01 2008-08-29 Тева Фармасьютикал Индастриес Лтд. TIZANIDINE COMPOSITIONS AND TREATMENT METHODS USING COMPOSITIONS
US20070042041A1 (en) * 2005-08-17 2007-02-22 Board Of Trustees Of The University Of Arkansas Drug-surfactant complexes for sustained release
EP1965787B1 (en) * 2005-11-30 2013-04-10 Endo Pharmaceuticals Inc. Treatment of xerostomia with a sulfur-containing antioxidant
EP1832572A1 (en) * 2006-03-08 2007-09-12 Stirling Products Limited Process for the enantiomeric enrichment of salbutamol and salbutamol precursors
WO2007117581A2 (en) * 2006-04-06 2007-10-18 Collegium Pharmaceutical, Inc. Stabilized transdermal bupropion preparations
BRPI0621778A2 (en) * 2006-06-13 2011-12-20 Cargill Inc large particle cyclodextrin inclusion complexes and methods of preparing the same
WO2008011194A2 (en) 2006-07-21 2008-01-24 Biodelivery Sciences International, Inc. Transmucosal delivery devices with enhanced uptake
US20090023637A1 (en) * 2006-08-30 2009-01-22 Parsons C Lowell Methods for detecting and treating interstitial cystitis
US8653066B2 (en) 2006-10-09 2014-02-18 Charleston Laboratories, Inc. Pharmaceutical compositions
US8969402B2 (en) 2006-11-15 2015-03-03 Steven A. Rich Combined acetylcholinesterase inhibitor and quaternary ammonium antimuscarinic therapy to alter progression of cognitive diseases
EP2049083A2 (en) * 2006-12-27 2009-04-22 Cargill, Incorporated Stabilisation by preparing cyclodextrin inclusion complexes
US20080275030A1 (en) 2007-01-19 2008-11-06 Sveinbjorn Gizurarson Methods and Compositions for the Delivery of a Therapeutic Agent
US20080216828A1 (en) 2007-03-09 2008-09-11 Alexza Pharmaceuticals, Inc. Heating unit for use in a drug delivery device
US20080283693A1 (en) * 2007-05-15 2008-11-20 Evans Michael J F Propulsion apparatus and system
TW200904485A (en) * 2007-05-18 2009-02-01 Alcon Res Ltd Phospholipid compositions for contact lens care and preservation of pharmaceutical compositions
WO2009061497A1 (en) 2007-11-07 2009-05-14 Svip5 Llc Slow release of organic salts of local anesthetics for pain relief
EP2240022B1 (en) 2008-01-09 2016-12-28 Charleston Laboratories, Inc. Bilayered tablets comprising oxycodone and promethazine
EP2265250A2 (en) * 2008-03-14 2010-12-29 Cephalon, Inc. Enhanced transmucosal composition and dosage form
ES2848841T3 (en) * 2008-03-27 2021-08-12 Helsinn Healthcare Sa Stabilized compositions of alkylating agents and methods of using these compositions
EP2311498A4 (en) 2008-08-05 2013-07-24 Medrx Co Ltd External preparation comprising fatty acid salt or benzoic acid salt of basic pharmacologically active component, and method for production thereof
TW201010727A (en) * 2008-09-03 2010-03-16 Alcon Res Ltd Pharmaceutical composition having relatively low ionic strength
KR20110056516A (en) * 2008-09-12 2011-05-30 크리티컬 파머수티컬스 리미티드 Improvements in the absorption of therapeutic agents across mucosal membranes or the skin
SI2343982T1 (en) * 2008-09-17 2017-08-31 Chiasma Inc. Pharmaceutical compositions and related methods of delivery
US8101593B2 (en) 2009-03-03 2012-01-24 Kythera Biopharmaceuticals, Inc. Formulations of deoxycholic acid and salts thereof
WO2011006012A1 (en) 2009-07-08 2011-01-13 Charleston Laboratories Inc. Pharmaceutical compositions
ES2553862T3 (en) * 2009-09-25 2015-12-14 Dr. Reddy's Laboratories Ltd. Formulations comprising triptan compounds
MX338110B (en) * 2009-09-25 2016-04-01 Reddys Lab Ltd Dr Formulations comprising triptan compounds.
US11337962B2 (en) 2009-09-25 2022-05-24 Upsher-Smith Laboratories, Llc Formulations comprising triptan compounds
US10668060B2 (en) 2009-12-10 2020-06-02 Collegium Pharmaceutical, Inc. Tamper-resistant pharmaceutical compositions of opioids and other drugs
WO2012000926A1 (en) * 2010-06-28 2012-01-05 Ratiopharm Gmbh Silodosin-cyclodextrin inclusion compounds
US20120237492A1 (en) 2011-02-18 2012-09-20 Kythera Biopharmaceuticals, Inc. Treatment of submental fat
US8653058B2 (en) 2011-04-05 2014-02-18 Kythera Biopharmaceuticals, Inc. Compositions comprising deoxycholic acid and salts thereof suitable for use in treating fat deposits
JP5856153B2 (en) 2011-05-10 2016-02-09 伊藤忠ケミカルフロンティア株式会社 Non-aqueous patch
US11786455B2 (en) 2011-05-10 2023-10-17 Itochu Chemical Frontier Corporation Non-aqueous patch
US9925264B2 (en) 2011-05-10 2018-03-27 Itochu Chemical Frontier Corporation Non-aqueous patch
BR112014006356B1 (en) 2011-09-19 2022-01-18 Orexo Ab SUBLINGUAL PILL, PROCESS FOR PREPARING IT AND ITS USE
CA2850024C (en) 2011-09-27 2020-07-07 Itochu Chemical Frontier Corporation Non-aqueous patch comprising lidocaine
US9901539B2 (en) 2011-12-21 2018-02-27 Biodelivery Sciences International, Inc. Transmucosal drug delivery devices for use in chronic pain relief
EP3079668A1 (en) 2013-12-09 2016-10-19 Durect Corporation Pharmaceutically active agent complexes, polymer complexes, and compositions and methods involving the same
WO2016126830A1 (en) 2015-02-03 2016-08-11 Chiasma Inc. Method of treating diseases
AU2016279798B2 (en) 2015-06-15 2021-07-08 Qaam Pharmaceuticals, Llc Glycopyrronium fatty acid salts and methods of making same
CN106880598B (en) * 2015-12-14 2021-08-31 山东新时代药业有限公司 Ezetimibe tablet
CA3055170A1 (en) 2016-03-04 2017-09-08 Charleston Laboratories, Inc. Pharmaceutical compositions
WO2017222575A1 (en) 2016-06-23 2017-12-28 Collegium Pharmaceutical, Inc. Process of making more stable abuse-deterrent oral formulations
CN106220562B (en) * 2016-07-29 2019-10-01 上海璃道医药科技有限公司 The new application of two kinds of quinoline ring class drugs
EP3704123A1 (en) * 2017-10-30 2020-09-09 Theracaine LLC Hydrophobic acid addition salts and pharmaceutical formulations thereof
KR20220140711A (en) 2020-01-13 2022-10-18 듀렉트 코퍼레이션 Reduced Impurity Sustained Release Drug Delivery Systems and Related Methods
KR20210150676A (en) 2020-06-04 2021-12-13 허승찬 e-commerce method using the Internet
US11141457B1 (en) 2020-12-28 2021-10-12 Amryt Endo, Inc. Oral octreotide therapy and contraceptive methods

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4722941A (en) * 1978-06-07 1988-02-02 Kali-Chemie Pharma Gmbh Readily absorbable pharmaceutical compositions of per se poorly absorbable pharmacologically active agents and preparation thereof
US5288498A (en) * 1985-05-01 1994-02-22 University Of Utah Research Foundation Compositions of oral nondissolvable matrixes for transmucosal administration of medicaments
US5288497A (en) * 1985-05-01 1994-02-22 The University Of Utah Compositions of oral dissolvable medicaments
GB9012663D0 (en) * 1990-06-07 1990-08-01 Erba Carlo Spa Galenic formulations containing cyclodextrins
IT1263831B (en) 1993-01-29 1996-09-04 Paolo Chiesi MULTI-COMPONENT INCLUSION COMPLEXES WITH HIGH SOLUBILITY CONSTITUTED BY A BASIC-TYPE DRUG, AN ACID AND A CYCLODEXTRINE
US5985316A (en) 1995-04-28 1999-11-16 Alza Corporation Composition and method of enhancing electrotransport agent delivery

Also Published As

Publication number Publication date
AU712546B2 (en) 1999-11-11
CA2259418A1 (en) 1998-01-22
JP2001508027A (en) 2001-06-19
EP1024833A1 (en) 2000-08-09
CN1230123A (en) 1999-09-29
IL127956A0 (en) 1999-11-30
KR20000023708A (en) 2000-04-25
US6255502B1 (en) 2001-07-03
WO1998002187A1 (en) 1998-01-22
KR20000022239A (en) 2000-04-25
BR9710289A (en) 1999-08-17
BR9710241A (en) 1999-08-10
WO1998002186A1 (en) 1998-01-22
AU3455297A (en) 1998-02-09
JP2000505090A (en) 2000-04-25
IL127955A0 (en) 1999-11-30
AU3455197A (en) 1998-02-09

Similar Documents

Publication Publication Date Title
CA2257860A1 (en) Inclusion complex containing indole selective serotonin agonist
US7202233B2 (en) Alprazolam inclusion complexes and pharmaceutical compositions thereof
EP0814844A2 (en) Thyroxine/cyclodextrin complexes and pharmaceutical compositions containing the same
WO2011064474A1 (en) Pharmaceutical composition containing strontium salt, vitamin d, and cyclodextrin
US20080015174A1 (en) Metabolic Disease Treatments
WO1998018827A1 (en) Inclusion complexes of beta-2-andrenergics for oral mucosal delivery
JP2006257091A (en) Pharmaceutical complex
KR20220156931A (en) Oral Terpene Cyclodextrin Inclusion Complex Vehicle
US20050059645A1 (en) Methods for the treatment of male and female sexual dysfunction
CA2427375A1 (en) Pharmaceutical dronedarone composition for parenteral administration
JPH10167958A (en) Loxoprofen sodium-containing oral cavity promptly soluble preparation and its production
JP2011246497A (en) Taste masking of oral quinolone liquid preparation using ion exchange resin
US20030083309A1 (en) Controlled release pharmaceutical
WO2004082589A2 (en) Nasally administrable, bioavailable pharmaceutical composition of loratadine
ZA200207221B (en) Alprazolam inclusion complexes and pharmaceutical compositions thereof.
CN1225018A (en) Inclusion complex containing indole selective serotonin agonist
JP2005527615A (en) A novel formulation for parenteral application of sodium channel blockers

Legal Events

Date Code Title Description
FZDE Discontinued